Pathogenesis of chlamydial pelvic inflammatory disease

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Fig 1. Scanning electron micrograph of the surface of the lumen of the mouse oviduct 10 days after the inoculation of 100 microlitres of saline (control). The surface looks healthy with many ciliated epithelial cells, which help move the ovum down the tube, in evidence. From Tuffrey et al., 1993. Fig 2. As Fig 1 except that the saline contained approximately 100,000 elementary bodies of the human chlamydial isolate, C. trachomatis NI 1 serovar F. The morphology of the epithelium is severely disrupted and large amounts of mucus block the lumen. From Tuffrey et al., 1993.

  • The major complications of pelvic inflammatory disease are caused by acute and chronic inflammation of the Fallopian tubes, salpingitis, leading to fibrosis and scarring. As in trachoma, Chlamydial genital tract infection is associated with the presence of lymphoid follicles, sometimes visible on colposcopy, containing transformed lymphocytes [Paavonen et al., 1987]. Functional damage to the tubes may affect egg transport, leading to implantation of the fertilized ovum in the tube rather than in the womb, i.e. ectopic pregnancy. Blockage of the tubes by scar tissue prevents egg transport and fertilization, leading to infertility if it is bilateral. Despite the importance of chronic inflammation, addition of anti-inflammatory drugs to antibiotic in an experimental model of salpingitis did not alter the pathology but led to decreased clearance of Chlamydial nucleic acid [Patton et al., 1997]. The necessity for rapid antimicrobial therapy to avoid tubal pathology is suggested by studies in the mouse which show that oviduct pathology and infertility due to Chlamydial infection cannot be reversed by antibiotic beyond about 12 days post infection [Tuffrey et al., 1994].

  • Repeated episodes of salpingitis lead to a greatly increased likelihood of infertility [see: PID complications but there is no hard evidence that any particular serovar is especially virulent. On the contrary, in a study of 424 women, the various clinical manifestations tended to occur at similar rates among the different serovars identified, suggesting these strains shared a similar pathogenic potential [Persson & Oser, 1993]. Repeated infections also play an important role in the pathogenesis of trachoma.

  • Repeated inoculation [3 times] of the macaque oviduct resulted in a mononuclear cell infiltrate dominated by CD8+ T-lymphocytes. Many of these were activated cytotoxic T cells [lay reader: part of the cell mediated immune system designed to kill infected or aberrant cells] as shown by the transcription of perforin [lay reader: a cell poison]. Fibrosis and the beginning of scarring was observed by the third infection. Genes for the following interleukins / cytokines [lay reader: chemical messengers between cells; part of the cell mediated immune system] were activated: interferon-gamma, interleukin-2 ( IL-2), IL-6, and IL-10; but not IL-4. This indicates a predominant T-helper 1 cell mediated immune response, associated with both protection and the inflammatory changes which induce scarring blockage of the tubes [van Voorhis, et al., 1997; see also: ]. Repeated infection increases the cell mediated immune response to Chlamydial and human heat shock protein [Witkin et al., 1994].

  • Interferon gamma production may favor chronic, persisting Chlamydial infection [see: Cell_Biology.PersistenceAndIfng; Antigens_Proteomics.HeatShockProteins]. Intravaginal infection of mice with C. muridarum [in old taxonomy: the mouse pneumonitis biovar of C. trachomatis] led to the shedding of high numbers of viable chlamydiae for 7-14 days, followed by a rapid decline correlating with the production of interferon-gamma. From 28-70 days post infection, all mice were culture-negative and developed characteristic hydrosalpinx of the oviduct [lay reader: swollen, fluid filled tube partially caused by tubal blockage]. In animals not shedding viable Chlamydiae, Chlamydial nucleic acid was still detected in most animals at days 21 and 28. Suppression of the immune response with either cyclophosphamide or hydrocortisone failed to restimulate shedding of viable Chlamydiae. The authors speculated that there was a nucleic-acid positive non recoverable form of the Chlamydiae which might persist but be beyond the reach of most reactivating triggers [Beale, 1997].
    [MEW comment: This is an old theory which has never been satisfactorily proven. Detection of Chlamydial DNA to 28 days might simply reflect the persistence of DNA and the sensitivity of nucleic acid detection methods. However it is unlikely chlamydial DNA would have persisted for as long in antibiotic treated animals; see: Patton et al., 1997; indicating genuine but limited persistence].

  • Interferon gamma production is thought to favour _Chlamydial_ heat shock protein production which in turn might trigger auto-immune attack on related host heat shock protein leading to tissue damage [see: Antigens_Proteomics.HeatShockProteins]. A study of 306 women with or without pelvic inflammatory disease found that antibody to Chlamydial heat shock protein (Chsp60) was significantly correlated with risk factors for pelvic inflammatory disease and occluded Fallopian tubes but not with C. trachomatis infection in the absence of pelvic inflammatory disease [Eckert et al., 1997]. [MEW comment: There are a number of similar studies, of which that by Antigens_Proteomics.HeatShockProteinsfor trachoma is particularly convincing as it attempts to control for hyperimmunization. The Eckert study does not mean that antibody to chlamydial or human heat shock protein plays a role in disease. It may be that long term / severe disease leads to hyperimmunization, with an expanding spectrum of Chlamydial antigens recognized which co-incidentally includes heat shock protein. Hence the correlation with IgG antibody to whole Chlamydiae. Antibody responses to heat shock protein might also be a proxy for more important cell mediated immune responses. see: Antigens_Proteomics.HeatShockProteins&cmi]. A rather different study compared antibody responses in 67 women with ectopic pregnancy compared with 45 women controls with uncomplicated interuterine pregnancy. Antibody responses to 13 synthetic peptides on chlamydial heat shock protein (Chsp60) were determined, some corresponding to Chlamydiae-specific regions of the protein and others to regions cross-reactive with human heat shock protein. Interestingly, women positive for antibodies reactive with both human and Chlamydial heat shock proteins had an increased prevalence over controls of salpingitis, pelvic adhesions, or a history of pelvic inflammatory disease (P < 0.05). In contrast, patients who were positive for only C. trachomatis antibodies or only human hsp60 antibodies did not differ from antibody-negative patients with respect to these categories [Sziller et al., 1998]. In a similar study, antibodies cross reactive to human and Chlamydial heat shock proteins were identified in roughly half of 129 patients with laparoscopically-verified pelvic inflammatory disease [Domeika et al., 1998]. Cell mediated immune responses [lymphocyte proliferation] are also produced to both Chlamydial heat shock protein (Chsp60) and to human heat shock protein in women with a history of C. trachomatis upper genital tract infections [Witkin et al., 1994]. Kinnunen et al., 2002, cultured T lymphocytes from the fallopian tubes of 5 patients with tubal factor infertility. Seventy-seven (34%) of the resulting 229 T-lymphocyte clones showed genus-specific reactivity against target C. trachomatis and C. pneumoniae elementary bodies. Approximately one third of these Chlamydia-reactive clones recognised Chsp60 and the majority of the clones were IL-10 producing and thus likely to be T-helper 2 lymphocytes.
    [MEW Comment: The extent to which the cloning methods may have biased results is not clear, but the results do indicate that significant CD4+ T cell responses occur to Chlamydial heat shock protein. This response may be ineffective against Chlamydiae, because T-helper 1 rather than T-helper 2 lymphocytes are associated with protect immunity against Chlamydiae].

  • The anaerobic [lay reader: oxygen intolerant] bacteria responsible for bacterial vaginosis are frequently associated with Chlamydiae or gonococci in upper genital tract infection in women [Paavonen et al., 1987] and appear capable of causing endometritis in their own right [Hillier et al., 1996]. In the rat model, gonococci or C. trachomatis initiate infection but do not produce abscesses in the absence of anaerobic bacteria. Microorganisms not inoculated were also recruited into the infectious process, probably gaining access to the peritoneal cavity via the lower genital tract or by transmucosal migration from the intestinal flora [Cox et al., 1991]. [MEW comment: These are important observations suggesting that lower genital tract anaerobic bacteria may act co-operatively with STD pathogens to produce severe pelvic inflammation, possibly justifying the inclusion of anti-anaerobe agents in treatment].

  • In human fallopian tube organ culture, C. trachomatis differs from gonococci in that it infects both ciliated and non-ciliated epithelial cells, is less cytotoxic and does not damage overall ciliary function [Cooper et al., 1990; Ward et al., 1974]. The relative absence of pathology in human fallopian tube organ culture is one of the reasons for believing that the host immune response and the participation of anaerobic bacteria probably play an important role in the pathogenesis of Chlamydial pelvic inflammatory disease.

[MEW] Updated March 2002

NEXT: Perihepatitis

References

Beale, A. S. (1997). Does Chlamydia trachomatis MoPn enter a microbiologically-inapparent state during experimental infection of the mouse genital tract? Microbial Pathogenicity 22, 99 - 112.

Buchan, H., Vessey, M., Goldacre, M. & Fairweather, J. (1993). Morbidity following pelvic inflammatory disease. British Journal of Obstetrics and Gynaecology 100, 558 - 562. [Important paper showing that the consequences of pelvic inflammatory disease are not just infertility and ectopic pregnancy].

Cooper, M. D., Rapp, J., Jeffery-Wiseman, C., Barnes, R. C. & Stephens, D. S. (1990). Chlamydia trachomatis_ infection of human fallopian tube organ cultures. Journal of General Microbiology 136, 1109 - 1115.

Cox, S. M., Faro, S., Dodson, M. G., Phillips, L. E., Aamodt, L. & Riddle G. (1991). Role of Neisseria gonorrhoeae and Chlamydia trachomatis in intraabdominal abscess formation in the rat. Journal of Reproductive Medicine 36, 202 - 205.

Domeika, M., Domeika, K., Paavonen, J., Mardh, P. A. & Witkin, S. S. (1998). Humoral immune response to conserved epitopes of Chlamydia trachomatis and human 60-kDa heat-shock protein in women with pelvic inflammatory disease.Journal of Infectious Diseases, 177, 714 - 719. [Interesting methodological approach using defined peptide antigens].

Eckert, L. O., Hawes, S. E., Wolner-Hanssen, P., Money, D. M., Peeling, R. W., Brunham, R. C., Stevens, C. E., Eschenbach, D. A. & Stamm W. E. (1997). Prevalence and correlates of antibody to chlamydial heat shock protein in women attending sexually transmitted disease clinics and women with confirmed pelvic inflammatory disease. Journal of Infectious Diseases 175, 1453 - 1458.

Hillier, S. L., Kiviat, N. B., Hawes, S. E,. Hasselquist, M. B., Hanssen, P. W., Eschenbach, D. A. & Holmes, K. K. (1996). Role of bacterial vaginosis-associated microorganisms in endometritis. American Journal of Obstetrics & Gynecology 175, 435 - 441.

Kimani, J., Maclean, I.W., Bwayo, J.J., MacDonald, K., Oyugi, J., Maitha, G. M., Peeling, R. W., Cheang, M., Nagelkerke, N. J., Plummer, F. A. & Brunham, R. C. (1996). Risk factors for Chlamydia trachomatis pelvic inflammatory disease among sex workers in Nairobi, Kenya. Journal of Infectious Diseases 173, 1437-1444.

Kinnunen, A., Molander, P., Morrison, R., Lehtinen, M., Karttunen, R., Tiitinen, A., Paavonen, J. & Surcel, H. M. (2002). Chlamydial heat shock protein 60--specific T cells in inflamed salpingeal tissue. Fertility and Sterility 77, 162 - 166. [Interesting paper addressing the key area of T cell function in tubal factor infertility, a topic difficult to investigate]

Paavonen, J., Teisala, K., Heinonen, P. K., Aine, R., Laine, S., Lehtinen, M., Miettinen, A., Punnonen, R. & Gronroos, P. (1987). Microbiological and histopathological findings in acute pelvic inflammatory disease. British Journal of Obstetrics and Gynaecology 94, 454 - 460.

Patton, D. L., Sweeney, Y. C., Bohannon, N. J., Clark, A. M., Hughes, J. P., Cappuccio, A., Campbell, L. A. & Stamm, W. E. (1997). Effects of doxycycline and antiinflammatory agents on experimentally induced chlamydial upper genital tract infection in female macaques. Journal of Infectious Diseases 175, 648 - 654.

Persson, K. & Osser, S. (1994). Lack of evidence of a relationship between genital symptoms, cervicitis and salpingitis and different serovars of Chlamydia trachomatis. European Journal of Clinical Microbiology and Infectious Diseases 12, 195 - 199.

Sziller, I., Witkin S. S., Ziegert, M., Csapo, Z., Ujhazy, A. & Papp, Z. (1998). Serological responses of patients with ectopic pregnancy to epitopes of the Chlamydia trachomatis 60 kDa heat shock protein. Human Reproduction 13, 1088 - 1093.

Tuffrey, M., Woods, C., Inman, C. & Ward, M. E. (1994). The effect of a single dose of azithromycin on chlamydial infertility and oviduct ultrastructure in the mouse. Journal of Antimicrobial Chemotherapy 34, 989 - 999.

van Voorhis, W. C., Barrett, L. K., Sweeney, Y. T., Kuo, C. C. & Patton, D. L. (1997). Repeated Chlamydia trachomatis infection of Macaca nemestrina fallopian tubes produces a Th1-like cytokine response associated with fibrosis and scarring. Infection and Immunity 65, 2175 - 2182. Full article. [Acrobat]

Ward, M. E., Watt, P. J. & Robertson, J. N. (1974). The human fallopian tube: a laboratory model for gonococcal infection. Journal of Infectious Diseases 129, 650 - 659.

Witkin, S. S., Jeremias, J., Toth, M. & Ledger, W. J. (1994). Proliferative response to conserved epitopes of the Chlamydia trachomatis and human 60-kilodalton heat-shock proteins by lymphocytes from women with salpingitis. American Journal of Obstetrics & Gynecology 171, 455 - 460.

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Topic revision: r11 - 2011-03-29 - SanderO
 
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